RA: Publication Bias Alive and Well

Action Points

Note that this analysis of published and unpublished studies found that, at least in the rheumatoid arthritis literature, positive studies are more likely to be published than negative studies.

Be aware that the authors identified studies reflecting the participation of over 10,000 patients in clinical trials whose data have not been disseminated to the scientific community through publication.

Randomized trials of treatments for rheumatoid arthritis (RA) that have positive outcomes are still more likely to be published than those with negative results, despite the establishment of the ClinicalTrials.gov registry, researchers found.

The adjusted odds ratio for publication for studies with positive versus negative efficacy findings was 4.5 (95% CI 1.9-10.8, P<0.001), according to Nasim A. Khan, MD, of the University of Arkansas in Little Rock, and colleagues.

Positive trials also were more likely to see earlier publication (HR 1.9, 95% CI 1.2-2.9), the researchers reported online in Arthritis & Rheumatology.

"Publication bias remains a significant problem in RA randomized clinical trials," they wrote. And the effects of this are wide-ranging, affecting not only clinical decision-making and patient expectations but also guideline formulation and financial concerns such as insurance reimbursement.

ClinicalTrials.gov began registering studies in 2000, and in 2005 the International Committee of Medical Journal Editors determined that registration was a mandatory requirement for publication. The FDA also has called for registration for studies other than phase I trials. Sponsors are encouraged, and in some cases required, to publish results of registered studies.

To see if these efforts toward greater transparency have had an impact on publication bias, the researchers identified 143 RA treatment trials completed between 2005 and 2009, 48 of which had never been published but were found in searches of scientific meeting abstracts and other sources such as industry websites.

"These 48 unpublished trials together have enrolled the stunning number of 10,000 RA patients whose selfless contribution to medical science apparently has been lost because investigators did not want to proceed with publishing the data," wrote Robert B.M. Landewe, MD, PhD, of the University of Amsterdam, in an accompanying editorial.

A total of 70.6% of the trials were funded by industry and 29.4% by nonprofit organizations.

Positive outcomes were found for 67.4% of the published studies, compared with only 31.2% of the unpublished studies.

For only 15% of the studies were the results posted on ClinicalTrials.gov.

Only one-third of RA studies on ClinicalTrials.gov had been registered before the trials began, and almost 30% hadn't been registered until they had been finished.

The fact that some studies were only registered around the time of manuscript submission seemed to suggest that "investigators only comply with this requirement in order to get an article published," wrote Landewe.

In addition, although many of the major journals do require registration, a survey of 200 journals found that less than one-third mentioned the requirement in their instructions for authors.

Overall, the median times until publication were 30 and 49 months for positive and negative trials, respectively. The time to publication did improve over time, however, being 55 months for trials completed by 2005 and 34 months for those completed by 2009.

"It is quite apparent from our and other studies that clinical trial registration by itself does not guarantee timely publication of results," Khan and colleagues observed.

A "reasonable goal" for publication could be 1 to 2 years after studies are completed, they argued. This goal may more often be met with the growing practice of medical journals making accepted articles available online, they noted.

"Increasing realization of the limitations of existing mechanisms for transparency in conduct and dissemination of results of clinical trials has led to demands for alternative mechanisms such as disclosure of standardized Clinical Study Report involving FDA-approved drugs, limited access to masked patient-level data, or disclosure of FDA review of all new drug applications," they wrote.

Concerted efforts are needed on the part of physicians, scientists, the pharmaceutical industry, insurance companies, and patients to further limit the existence and impact of publication bias, they concluded.

Limitations included the inclusion of only RA randomized clinical trials, so the findings may not be generalizable to other areas of medicine, and the inability of the researchers to obtain outcome information for 16 of the unpublished studies.

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